Fat accounts for 3 to 5% of liver wet weight in a normal human liver. It would be called a fatty liver if more than ⅓ hepatocytes have steatosis histologically. The fat content may be up to 40 to 50% in some diseased livers. In general, fatty liver is actually relating to a group of diseases, for example from simple fatty liver (NAFLD) to steatohepatitis (NASH) and further developed to hepatic fibrosis wherein a considerable portion of people would eventually develop hepatic cirrhosis and a few people would eventually develop liver cancer. Thus, the development of medicaments for treating fatty liver has been highly valued.
In 1980, Jurge liudwig et al. reported hepatic steatosis in people who had low alcohol consumption per day. Over the next more than 30 years, researchers accumulated a large amount of evidences which can fully confirm this disease, such as the relationship between hepatic steatosis and obesity, and the clinical and biological differences including pathological morphological differences from alcoholic fatty liver. On this basis, the non-alcoholic fatty liver disease is identified as an independent disease. Further, researchers, especially in the past 10 years, have proven that steatohepatitis (NASH) is an independent and common disease that would develop severe diseases such as cirrhosis in a considerable number of people.
Due to lack of sensitive and specific diagnostic markers, the accuracy of epidemiological investigations of NAFLD is affected, and thus the epidemiological incidence of fatty liver is greatly underestimated. It is known that the sensitivity of ultrasound examination is higher than that of liver function test. In America, it was found that 20 to 30% of the population has over-standard triglyceride level in liver through measurement with magnetic resonance. Similar incidences were reported in recent years for Japan and China, while incidences vary from region to region in Africa with a general incidence of 10 to 20%. Thus, it is estimated that approximately 1 billion people have fatty liver worldwide. In recent years, fatty liver has risen from the third place to the first place among chronic liver diseases in incidence. According to statistics in America, the percentage of fatty liver among chronic liver diseases rose from 47% to 75% during the years 1988 to 2008. During this period, the five metabolic disease risk factors also had significant increase correspondingly, for example, the incidence of obesity rose from 24% to 33%, the incidence of visceral obesity rose from 35% to 51%, the incidence of type II diabetes rose from 5.6% to 9.1%, the incidence of insulin resistance rose from 2.3% to 3.5%, and the incidence of arterial hypertension rose from 22% to 34%. Meanwhile, fatty liver is closely related to these factors. The prevalence of obesity in patients with fatty liver is between 30 and 100%, and that of type II diabetes is between 10 and 75%. In Germany, the incidence of obesity in adults was 11.5% in 2000, and was 14.7% in 2010. In addition to the above factors, age and sex also play an important role. For example, the incidence of fatty liver is significantly higher in male older subjects and in subjects of Spanish ethnic origin. Therefore, many countries have issued clinical practice guidelines for non-alcoholic fatty disease/non-alcoholic fatty liver disease for NAFLD in recent years, and some research associations such as those in China, America, and Japan have issued their own guidelines.
In view of the high incidence and poor prognosis of fatty liver, various research institutions and pharmaceutical enterprises have begun to develop corresponding drugs. Since NAFLD is usually associated with metabolic disorders such as visceral obesity, IR, type II diabetes and dyslipidemia, the treatment would aim not only at liver disease, but also at these related metabolic disorders at the same time. However, the treatment could focus on the treatment of NAFLD if no related metabolic disease is accompanied by.
At present, effective methods for treating NAFLD/NASH include lifestyle interventions, surgical treatments, and drug treatments. The treatment of NAFLD depends on histopathological changes according to the treatment principle for NAFLD/NASH. If it is suggested through liver biopsy that a patient has only simple hepatic steatosis and no steatohepatitis or hepatic fibrosis, the patient would be recommended to change lifestyle, lose weight and increase physical activity. If a patient has severe obesity, surgery for treatment of obesity would be considered. For patients with NASH, the treatment depends on underlying diseases. If a patient has other underlying metabolic disorders such as IR (insulin resistance), type II diabetes, dyslipidemia, hypertension and obesity, these concomitant diseases need to be treated simultaneously.
For drug intervention, the drug treatment of NAFLD/NASH mainly directs to metabolic syndrome-related diseases, such as obesity, type II diabetes, dyslipidemia and hypertension. By now, there is no definitely effective drug for fatty liver, although many drugs have been used for evaluating the treatment of NAFLD/NASH. That is, the drugs that have been marketed have not been proven to be capable of treating fatty liver (Clujul Med. 2016, 89(1): 19-23; Drug Des Devel Ther, 2015, 20(9): 4835-4845). The development and research of drugs for treating fatty liver is booming currently.
During the exploration of drugs for treating fatty liver, there are mainly the following types of researches: 1. anti-fibrotic drugs used for treating NASH, such as Cenicriviroc, an inhibitor of C—C chemokine receptor types 2 and 5 (CCR2 and CCR5), which has been demonstrated to be capable of preventing and treating hepatic fibrosis and cirrhosis; 2. derivatives of bile acid, which usually are liver-related targets and have certain effect in treating non-alcoholic steatohepatitis according to the clinical data currently published, such as aramchol from Galmed Pharmaceuticals, which is a derivative obtained by combining fatty acid and bile acid; 3. galectin family, which can specifically recognize galactoside, such as GR-MD-02 which is a candidate inhibitor of galectin announced by Galectin Medical company to be capable of treating fatty liver and hepatic fibrosis; 4. peroxisome proliferator-activated receptor (PPAR), which is an important target for regulating sugar and lipid metabolism in vivo and improving insulin sensitivity, and good results have been achieved for screen of PPAR agonist compounds in the recent researches of fatty liver; 5. bile acid receptor FXR agonists, which are also in-depth researched for non-alcoholic fatty liver, and in which FXR is a member of the nuclear receptor family and involved in the metabolism of bilirubin. Preclinical studies showed that the activation of FXR can protect against liver damages induced by cholestasis. Obeticholic acid (OCA) is a derivative of chenodeoxycholic acid in natural bile of human, and has an agonistic effect on FXR 100 times more than chenodeoxycholic acid. It is shown by preliminary clinical trials that obeticholic acid is safe and effective. With further researches, obeticholic acid was approved by FDA as a drug for cholestatic cirrhosis (PBS) and had been marketed. However, obeticholic acid has serious side effect of itching, and the phase II clinical results obtained from fatty liver treatment in Japan are different from its expected effect. It was shown in Japan clinical trials that the effective dose of obeticholic acid was increased due to ethnic differences of patients, and the proportion of people with severe side effect of itching was as high as 70 to 90%. The clinical trials of fatty liver treatment are expected to finish in 2022 and final results could be known then.
In summary, obeticholic acid, a derivative of bile acid salt, has side effects of increasing blood lipids over a period of time and other side effects caused by bile acid salt, such as severe itching.
The present invention relates to novel aminoacetophenone-based compounds, and further derivatization and optimization thereof. Rats were fed with high fat diet to induce severe fatty liver, and administered with the optimized compounds to carry out efficacy researches. It was found from hepatic tissue pathological sections that hepatocyte steatosis, infiltration of mixed inflammatory cells in hepatic lobules, or cell infiltration with inflammation in the lobules severer than that in portal areas and fibrogenesis are significantly reduced as compared with those of the livers of rats in the model group. With comparison, it was demonstrated that the series of compounds of the present invention have clear and significant therapeutic effects on fatty liver, and also have significant hypolipidemic activity. By now, there is no report that similar compounds have related pharmacological effects. The present invention, for the first time, screened out a series of compounds having therapeutic effects for fatty liver through structural optimization and pharmacodynamic tests, thereby producing significant contributions to the field of treatment of fatty liver diseases.
Further, we found Compounds 13 and 14 of the present invention had obvious effects on weight loss by employing ob/ob obese diabetic mice and nutritive obesity C57 mice.